Project Summary This research proposes a novel and innovative link between the ER stress response (ERSR) and hypertension in atrial myocytes. During pressure-overload and ischemia the synthesis and folding of proteins in the ER is perturbed leading to ER stress in the cardiac myocyte, and potential cardiac dysfunction. When ER protein folding is impaired, hundreds of genes encoding the ER protein folding machinery are induced by the primary adaptive cardiac sensor, ATF6. Increased blood pressure and plasma sodium stimulate the secretion and cleavage of pro-ANP to form the adaptive cardiac effector, ANP, which promotes salt excretion and vasodilation, which homeostatically restore blood pressure. Recently, we identified 381 genes that were specifically induced by ATF6 in the mouse heart. Of the genes identified, 30 encode proteins known to be secreted by the conventional secretory pathway. Further analysis revealed additional genes encoding proteins that are essential elements of the secretory pathway. One such protein, SNAP23, is required for secretory granule exocytosis in neurons and to co-localize with ANP-containing secretory granules in the atria. The novelty of this finding lies in the fact, that although global protein synthesis and secretion are down-regulated during the ERSR, expression of proteins required for the regulated secretion of adaptive proteins through the conventional secretory pathway is increased. The hypothesis addressed in this proposal is that the adaptive cardiac sensor, ATF6 is required for the proper secretion of adaptive cardiac effector, ANP from atrial myocytes, and that a robust ATF6-ANP axis is required for cardiovascular homeostasis. To address this hypothesis, the specific aims are to 1) examine how ATF6 gain- and loss-of-function affect ANP secretion from cultured rat and mouse atrial myocytes, and from the mouse heart, and 2) assess the effects of ATF6 gain- and loss-of-function in a clinically relevant mouse model of hypernatremia-induced hypertension. These aims will be achieved using cultured cardiac myocytes for mechanistic studies and in the mouse heart using a novel ATF6-floxed mouse line to conditional knockout the gene in cardiac myocytes and a selective small molecule activator of endogenous ATF6. In addition to determining the importance of the ATF6-ANP axis, this study will assess the viability of ATF6 as a potential therapeutic target for ANP-based imbalances in hypertensive stress and cardiovascular homeostasis.